TREM-1 biology

The innate immune system constitutes the first line of defense against invading microbial pathogens and relies on a large family of pattern recognition receptors (PRRs), which detect distinct evolutionarily conserved structures on pathogens, termed pathogen-associated molecular patterns (PAMPs), but also danger-associated molecular patterns (DAMPs). Stimulation of PRRs initiates the inflammatory reaction which promotes in turn the elimination of infectious agents and/or the induction of tissue repair.

TREM-1 (Triggering receptor expressed on myeloid cells-1) is an immunoreceptor that belong the immunoglobulin superfamily, expressed on innate immune cells, monocytes/macrophages and neutrophils, and is well known to be implicated in the amplification of pathogen and danger signals. Indeed, the TREM-1 function is to modulate/amplify, rather than initiate, inflammation, by synergizing with PRRs and leading to for the production of an exuberant acute immune response. The release of a soluble form of TREM-1 constitutes a negative regulatory mechanism.

Although the role of TREM-1 was first identified in infectious diseases, and in particular as an amplifier of the systemic inflammatory response syndrome associated with sepsis, it now appears that this protein is also crucial in both acute and chronic aseptic inflammation. Besides, recent findings at INOTREM suggest an important role of TREM-1 in cardiovascular diseases.

Several preclinical studies have now proved the potential benefit of inhibiting the TREM-1 pathway. The advantage of modulating TREM-1 is that such an approach does not totally abrogate the inflammatory response, which is essential for instance for bacterial clearance. In addition, a sustained and uncontrolled inflammatory response is the main cause of the harmful effects observed in patients. Interventions targeting the mechanisms leading to that uncontrolled inflammatory response positively affect disease progression and long-term outcomes.

sepsis

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection and is associated with an in-hospital mortality greater than 10%. Septic shock is the ultimate complication of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone. Patients with septic shock can be clinically identified by a vasopressor requirement. This combination is associated with hospital mortality rates greater than 40%.

Although poorly recognized, sepsis represents a large public health burden, as it is one of the most common diseases leading to death. With an incidence of approximately 150 cases of hospital treated severe sepsis per 100,000 in the “western” world (USA, Europe, Australia) and mortality rates of almost 30%, severe sepsis is a leading cause of death accounting for up to 5 million deaths worldwide.

Today there is no specific causal treatment for sepsis, and previous attempts to develop treatments have failed, mainly due to (1) The relative weakness of the preclinical experimental data package (both primary concept, biology and proof of concept using non-relevant animal experiments), (2) The inability to select the patient population that is most likely to respond favorably to the test treatment and (3) The need of alternative clinical trial designs such as adaptive design, longer periods of observation, alternative endpoints to all-cause mortality and a focus on organ failure as an endpoint.

INOTREM is now initiating first-in-man studies for the clinical development of its targeted therapy against sepsis: MOTREM.

Acute myocardial infarction (AMI)

Cardiovascular diseases (CVD) are the leading cause of mortality worldwide, claiming around 2 million in the European Union. Recent data indicate that up to 80% of all healthcare expenditure in Europe is allocated to chronic diseases, with CVD alone being estimated to cost the EU economy more than 196 billion € every year.

Myocardial Infarction (MI) or Acute Myocardial Infarction (AMI) is one of the main consequences of atherosclerosis and alteration of blood flow due to atherosclerotic plaque erosion and rupture, which lead to clotting cascade and coronary occlusion. MI thus occurs when myocardial ischemia exceeds a critical threshold and triggers an immune response in order to activate repair mechanisms designed to maintain normal operating function and homeostasis.

There is today a large body of evidence showing that innate immunity plays a crucial role in the pathophysiology of post-ischemic cardiac tissue remodeling. Similarities exist between septic states and AMI, as an innate immune response is quickly initiated by tissue injury, whether related to pathogens or other sterile aggressions such as ischemia. However, no therapeutic strategy that specifically targets these pathways is yet available. Optimal outcome after MI depends on a coordinated healing response in which both debris removal and repair of the myocardial extracellular matrix play a major role, positioning leucocytes as central protagonists and potential therapeutic targets in tissue repair and wound healing after MI.

We recently discovered the role of TREM-1 during the pathophysiology of MI. We identified that TREM-1 has a major role in controlling inflammatory cell recruitment and activation after MI. MOTREMTM could thus become a next-generation therapeutic approach in the management of Acute Myocardial Infarction, and is part of our clinical programs.